la antigens play a multi-faceted role in regulating the immune response. They have been implicated in immunological processes such as antigen presentation. T cell-B cell cooperation, and thymic education to tolerance and MHC restriction. But details of the mechanisms involved remain obscure. As one approach to elucidating some of these details, we propose to create transgenic mouse lines that express Ia antigens in only specified compartments of the immune system. Lines that lack E complex on the thymic epithelium, on thymic and peripheral macrophages, and on B cells have already been derived. By injecting genetically engineered Ek alpha genes into embryos, we will attempt to create still other mouse strains that exhibit novel patterns of Ia expression. Each strain will be carefully studied to establish the precise pattern of transgene expression and to evaluate the animals' immune capabilities. Important immunological questions can be addressed; in particular, we will ask in what compartment(s) E complex must be expressed in order to promote self-tolerance, to protect NOD mice from diabetes, and to influence the T cell repertoire expressed in the periphery. Answers to these questions have important implications for the many human diseases linked to the major histocompatibility complex (diabetes, multiple sclerosis etc.).